Wednesday, September 24, 2014

We are constantly hearing about 3D printing in the media. Whether people are making 3D-printed cars, guns, or even organs, this technology is becoming wild with the thousands of different applications. My new favorite: a 3D printed brain.

A hemispherectomy is a [scary] surgical procedure in which an entire hemisphere of your brain is either entirely removed, partially removed, or surgically disconnected (termed: functional hemispherectomy because all electrical influence of the diseased hemisphere is removed) from a healthy hemisphere in order to protect the healthy brain from damage (picture below is an example brain scan of a 7-year old girl who underwent the procedure, note what is missing!).

Image Source: http://www.dailymail.co.uk

The removed or disconnected hemisphere is epileptic and damaging the healthy hemisphere of the brain. I have always found this procedure to be so barbaric but also astonishing at the same time. An entire half of your brain is removed! Unfortunately, this is currently one of the only effective treatments for such intractable epilepsies. But, what is so phenomenal about this is that not only do patients not present with any long-term deficits in language or intelligence, their IQ often improves. On average there is an increase of 10 IQ points!

Before I get into what all of these results mean in terms of the implications of brain function and its amazing plastic nature, I want to review some of the basic neuroanatomy that is truly incredible with human brains. Gyrencephalic brains (of which human brains are included) are often considered to be more ‘complex’ and contain a vast number of folds to obtain the surface area required for their high neuron count. Lissencephalic or ‘smooth’ brains are often observed in animals that are considered to be more primitive (e.g. rodent brains) in nature and have lower neuron counts since the brain does not need the surface area to accommodate for an increased number of neurons. Now, why is this important? Brain tissue is incredibly weak! It’s really hard to convey this idea to people who haven’t held an unfixed brain. And, this is important for part of the story later when I talked about how the tissue is actually removed. Here is a good example of an unfixed human brain:

Watch this video because it is pretty incredible; it is a demonstration of a human brain being handled immediately following its removal during an autopsy. It is important to understand how weak the brain is because if the brain were resting on any part of your skull, it would be damaged. As you can see in this video demonstration, just from having an unfixed human brain set on a table, it has deformed the tissue and compressed it immediately. So, how does the brain stay undamaged inside of the skull? Cerebrospinal fluid typically ‘floats’ the brain and this prevents it from being damaged. And, in order to prevent the cerebral hemispheres from crashing into each other or the cerebellum, we have evolved some incredible structures that are rarely covered in introductory neuroanatomy courses.

Inside the human skull we have what are called the falx cerebri (pictured below), a structure typically present within the skulls of species that possess gyrencephalic brains. These incredible extensions of the dura mater, a protective covering of brain tissue, plunge down in between the cerebral hemispheres to block them from damaging each other. An additional projection extends from the skull wall to separate the hemispheres from the cerebellum. These structures are so rigid that during an extreme trauma such as a car accident or a blast-traumatic brain injury, the rotational forces generated can cause the brain matter to contact the falx cerebri and sheer the brain tissue like a hot knife through warm butter. Brain tissue is that weak. Now, imagine the incredible task of the neurosurgeon. In the more commonly performed modern procedure, the functional hemispherectomy, the neurosurgeon must navigate and sever all connections of epileptic hemisphere from the healthy half of your brain. As I am sure you can imagine, an incredible number of complications are associated with this surgical procedure given the construction of the inside of the human skull. The entire skull cannot be removed and several sites are required to be severed in order to obtain complete functional disconnection of the unhealthy hemisphere. Normally, this is done with some mapping by a magnetic resonance imager but, in some ways, one might argue the operation is done somewhat blindly as there are enough individual variations in brain anatomy to cause problems.

On September 3rd, The Verge reported the incredible story of Gabriel Mandeville. At the age of 5 months, Gabriel started experiencing incredibly debilitating seizures and they only continued to get worse. After several treatment attempts failed, Gabriel’s neurologists quickly decided the only treatment option was a functional hemispherectomy. Understanding the incredible risk associated with this surgery, Boston Children’s hospital had a 3D printer replicate Gabriel’s brain to give the surgeon a practice run. Part of a growing program at Boston Children’s and Harvard’s Hospital, the Pediatric Simulator Program (called SIMPeds: http://simpeds.org/) creates extensive simulations for various procedures to allow physicians and surgeons to practice these operations in advance of the real thing. A variety of 3D printed objects are being produced to simulate more common procedures and for those as rare as the hemispherectomy performed by Gabriel’s neurosurgeons.

The happy ending to this story is that Gabriel is now seizure free. But, I still haven’t hit the nail on the head as to why I think this is an incredible story that gives us such powerful information about the brain. An entire half of a brain is either completely or partially removed during this uncommon surgical procedure. It seems that either through abnormal development, perhaps due to the presence of the diseased hemisphere, the healthy hemisphere is able to take over seemingly all of the functions of the diseased hemisphere. Again, further demonstrating that the neuromyth that we have hemispheric dominance is not true (if the myth were true all of the functions associated with some particular hemisphere should be completely lost). It’s almost hard to believe that we can still do so much with that much loss. Even further, the average improvement in IQ by 10 points is remarkable and suggests that the diseased hemisphere was almost putting some kind of brake or training wheels on the healthy one and hindering its normal function.

The brain is truly the most remarkable organ. For most people, it might seem impossible that our brains could adapt to such a trauma but it prevails for reasons we are far from completely understanding. A fact that makes this field so exciting; so much is left to be learned. 3D printed ‘practice brains’ are making this procedure far safer and a more viable option to let the healthy brain do what its designed to do best during development: thrive.

NeuroscienceDC

References:

The Verge, "Doctor turns to 3D printers in a race to save a toddler's mind." September 3rd, 2014: http://goo.gl/gV7a5g

Tuesday, June 17, 2014

Similar to the once wildly popular anime, Dragon Ball Z, science too has its own sagas.

Webster defines ‘dogma’ as, “a belief or set of beliefs that is accepted by the members of a group without being questioned or doubted.” Science is no different than any other field in terms of having its own dogmas. Anyone who has taken a biology course is probably familiar with the central dogma of molecular biology. In 1958 it was thought that information transfer occurs in the following order:

As with most ‘rules’ in biology, viruses tend to break them [and they do so in some of the coolest ways]. Like Apple’s slogan, “There’s an app for that,” there’s often a virus that breaks a biological rule you think you know (Author’s note: if biology textbooks pick up the phrase, “There’s a virus for that” you can say you saw it here first). The discovery of RNA-based tumor viruses demonstrated that viruses with an RNA-based genome can actually insert their information into the nucleus in a fashion reverse that of the central dogma (RNA --> DNA). This discovery led to a major change in the way we think about the flow of biological information within the cell. Questioning some of the most basic assumptions about life have led to amazing, and important discoveries.

In neuroscience, a traditionally held dogma basically states that no new neurons are produced in the adult brain. This dogma is part of a constantly evolving saga in neuroscience: the neurogenesis saga. Some may have heard of the Neuromyth that whenever you drink alcohol, you lose brain cells. Aside from being dispelled as a neuroscience myth, logically this doesn’t seem to make sense. If this were true, this would mean the brains of a lot of college freshman everywhere might rapidly shrivel to nothing during their first semester in college. Thankfully neither of these pieces of information are true. Our brains are capable of producing new neurons, a processed called adult neurogenesis and alcohol–for the most part–does not kill them. There are two brain regions that are now associated with producing newborn neurons in the adult brain: the dentate gyrus of the hippocampus and the subventricular zone.

As it often happens in science, the story evolves and gets more complicated in light of new data. Ernst and colleagues published a paper in Cell that provides strong evidence that neurogenesis also takes place in the adult striatum–a structure well-known for its involvement in motor control. This begs the question, why would there be a need for newborn cells in the adult striatum? Huntington’s disease is typically associated with damage to the striatum and abnormal movements called chorea. Many more studies will need to be conducted to infer the role of striatal neurogenesis, but it is interesting to note that the authors of this paper also analyzed post-mortem brain tissue of patients who had Huntington’s disease. They found a dramatic reduction in the number of newborn cells produced in the striatum of these patients present in the disease. Why is this happening? It is unclear but the discovery could play an important role in understanding Huntington's disease and assist in treatment development.

In the hippocampus, a structure extremely well-known for its role in learning and memory, the answer for why there would be a need for newborn neurons in the adult might seem a little more straightforward. And, as it turns out, it appears that newborn neurons in the adult hippocampus are required for the formation of new memories. But, interestingly, the production of too many newborn neurons in the hippocampus may paradoxically induce forgetting. In a paper recently published in Science, Aker and colleagues suggest an explanation for the phenomenon of infantile amnesia. Don't vividly remember the first few years of your life? Based on the interesting evidence presented in the paper, the authors suggest that the production of new cells within the hippocampus actually regulates forgetting. When we are newborns, the process of neurogenesis is occurring at an alarming rate and because of this, we are not able to retain any of our first memories during early life. I found this particular study to be fascinating because I think the kinds of scientific questions like, "Why can't I remember being 2 years old?" are unique to neuroscience. Moreover, the fact that we're able to answer these questions now with modern lab techniques make this such an exciting field. I'm anxious to see where the neurogenesis saga goes next.

Saturday, March 22, 2014

The rich are not the only 1%ers. Roughly 1% of the world has
epilepsy. Epilepsy is one of the most common neurological diseases in the world
and unfortunately, up to one-third of these patients are resistant to
the current anti-epileptic medications. For these patients, there is little
recourse. Epilepsy surgery, though an extreme form of medical intervention is
one of the only options for patients whose epilepsy is drug-resistant. This past November, the FDA approved an implantable device made by NeuroPace that acts–as you might've guessed by the name–similar to a pacemaker (pictured below).

Once NeuroPace detects the onset of abnormal electrical activity, it delivers short rounds of stimulation to prevent seizure activity from starting or arrest it in its tracks. This device is currently approved by the FDA for the treatment of partial epilepsy that is resistant to 2 or more current antiepileptic medications. Partial epilepsies are those that have seizures that do not spread to or occur throughout the entire brain but are localized to a specific area; the seizure focus. This device is not designed to treat those seizures that do spread throughout the brain (generalized seizures).

The advent of this device highlights some of the more recent advancements for patients with this debilitating disease. But, this also represents hope for people who have a certain stigma associated with their disease. In the United States, patients with epilepsy have significant challenges. Depending on the state you live, there can be rather severe but understandable restrictions on how long you must be seizure-free before a driver's license may be issued (see this article for a review on driving issues and epilepsy). Alarmingly, the diagnosis of epilepsy can also be used in the consideration of divorce proceedings and these patients may be denied custody of their child based on this diagnosis.

Depending on your culture and part of the world you live, the diagnosis of epilepsy can be a mark of disgrace, or even considered a form of madness. Attitudes towards disorders such as epilepsy are changing but, unfortunately in some languages, the word used for epilepsy derives from words that are demonstrative of the cultural attitude towards this disease. For example, in Chinese the word for epilepsy is 癲癎 or dianxian, a word for madness. In Japanese, the word epilepsy is てんかん (tenkan) which also means madness. In a recent article in Epilepsia, Kim and colleagues discuss these cultural stigmas regarding the diagnosis of epilepsy in Asia and in an attempt to change these attitudes, Korea is leading the way by altering their current name for epilepsy: 간질 (Gan-jil) meaning mad sickness to 뇌전증 (Noi-jeon-jeung) a word meaning cerebroelectric disorder.

Changing the legal and cultural attitudes towards people with epilepsy will help these patients seek the medical treatment they desperately need. Treatments like the device by NeuroPace represent a significant advancement in the treatment of drug resistant epilepsies.

For our first episode our special guest is Katherine Bryant (Twitter: @EvoNeuro). Katherine is neuroscience PhD student at Emory University studying primate cortical evolution, the main topic of conversation during our episode. Specifically we talk about the visual system across different primate species and how this system may have evolved. We also have a short chat about freedom of speech and activism within academia. I hope everyone enjoys this first episode and I am very excited for the rest of the season 1. I won't give away all of the guests but one of the our other guests is the famous neuroscientist, Dale Purves who is not only an expert in vision but has written one of the canonical introductory neuroscience textbooks used by many undergraduate and graduate neuroscience programs.

Wednesday, November 27, 2013

Steven
Miller: How did you
come to work with Nature with your background in molecular neuroscience?

Noah Gray: I did a
post-doc after my graduate work with Karel Svoboda for three years and I got to
the point where I wasn’t quite done with the bench. But, I felt like I needed a
break to recharge the batteries and try something else before I went on the job
market because I thought I wanted to stay in academia. There was a job opening
at Nature Neuroscience that I happened to come across while reading Nature and
I thought it was a great fit for what I was looking for. It was like a
mini-sabbatical to get away from the bench but not out of science–keeping that
foot in the door. I figured I had about a year before academia would reject me.
The plan was about nine months in, I would start looking for a second post-doc.
But, I enjoyed the job a lot, I enjoyed Nature Neuroscience. The job at Nature
opened up while I was in this point where I had to make the decision of closing
the academic door. I got that job and now I have been at Nature for over five
years. It was almost by accident but I like it.

SM: You think it has been too long for you to go back to the bench if you wanted?

NG: That is just
my impression. As everybody knows it is really challenging to get a
tenure-track position these days. So, if a decision is between me who is
two-years away from the bench who had publications a couple of years earlier
and another scientist who has similar publications but is at the bench now… I
feel like I just had a very short window of leave to be able to come back and
be forgiven. If I wanted to go back and do bench work now, I could go back as a
technician, I could go back as a staff scientist or something. But, getting my
own lab would most likely be a failed endeavor. I probably wouldn't find
someone to hire me. That’s what I mean by that short window.

SM: I had a
really interesting conversation with Allan Jones of the Allen Institute for Brain Science and he said how he does not like the position of post-doc. He
thought that it shouldn't exist and that our scientists should be able to come
out of a PhD program being able to run a lab. Dr. Jones also said that the
position was started over 30 years ago when there was a similar job market to
now–very limited assistant professor positions available.

NG: I agree. I
am a big fan of maybe trying to do create something like that again, some kind
of new position. I don’t know the European models or Chinese models that well
but I feel like there are other options other than a lab head in other
countries. In the U.S. there are unique individuals who carve out a unique
position within their institute, whether they call them research scientists,
staff scientists, or super post-docs, you name it. Some people don’t want to
have their own lab, they don’t want to worry about grants, they just want to do
bench science and I think that is a valuable resource for any number of us.
People would kill for that. But the problem is that those positions aren't supported by the university because those positions by definition should be a
staff position at the university. When they’re linked to the lab it could be a
little dangerous for the person because if the lab leaves or it loses its
funding then that person is out of a job. Whereas if it were a staff position, you
could find another lab that could support your salary and find work. I feel
like we are at a position where with the number of scientists we’re training that we
need another evolution. We need another position at the university-level to do
this kind of thing for the people who just want to do good science and let the
people who want to write the grants, write the grants.

SM: I had an
interesting conversation with the BrainFacts.org team regarding what the
friction might there be for attracting viewership to science websites. Do you think
the friction for types of jobs you mentioned and their lack of support from the
academy might be due to an attitude problem?

NG: I don’t
know. I guess like with anything… we have our debates about open access, now
new debates about data deposition, the culture needs to change. It’s a chicken
and egg problem. The funding agencies need to say we are going to offer funding
modules for these positions and universities can apply for the funding. Or the
universities can take the position to say we are going to start hiring these
individuals and our scientists will start building new modules for these
positions into their grants. I don’t know who needs to do that first but somebody
needs to make a move in order to make something like this to happen as long as
there is a market for it. I’m speculating that there is a market for some
alternative within academia that isn't PI. There’s enough people out there that
like being in academia but their only option is to be a PI and they just don’t
want to be a PI. And, there’s nothing wrong with that but there’s no other
option.

SM: If NIH
provided the opportunity to apply for this kind of funding, people might adapt
to this idea as they would be able to lead the way as one of the primary
sources of grant money.

NG: You could
make an argument too that this could all link together with discussions about
how science is assessed. Right now there is a big debate on whether post-publication
peer-review is the future. There’s an argument that it is not really being taken
up by scientists so that must mean they don’t want to do it or don’t find it of
value and that’s not the case. Right now there is no value in doing the common
post-publication review because you don't get any credit for it. Hiring
committees and tenure committees should spend the time to review and give
credit for these contributions to science. Faculty do their teaching, they do
their service to their university, they bring money in with grants and they
have their publications. It would be great to have a fifth thing in there that
is determining what contributions you have brought to your field in general.
Usually that is assessed by how many talks were you invited to give, how many
papers you published. There’s no reason why your contributions to the
post-publication peer review process couldn't be a part of that whole oeuvre of
work as a scientist in order for the universities to determine whether you
merit tenure, or hiring or whatever. You could imagine those positions of staff
scientist or bench scientist where they don’t have to write grants could
instead make a valuable contribution to the post-publication review process.
It’s not that they don’t have good ideas; they just don’t want to write grants.
They wanted a more relaxed scientific career. Being a PI is very stressful.
Writing grants is very stressful–especially right now–and these people did not
want that but they wanted to stay at the bench. There’s nothing wrong with
that. I think these things could help other areas that there’s a debate in. If
there were positions in academia that would allow for post-publication peer
review to grow, maybe these staff scientist positions could offer that
opportunity.

SM: Maybe Nature
should offer an award for people who do that frequently.

NG: Ha ha ha.
That’s above my pay grade but I can make that suggestion.

SM: Speaking of
funding, there’s been some talk on NIH going anonymous in their grant review
process. Do you think that should be done–especially with the challenge in
terms of how many grants are available now?

NG: I think it
should be done only because I've heard enough anecdotal stories on both sides
of this coin. One of the most common stories being, ‘Well… I don’t know who
this guy is so I don’t know if he knows how to do this kind of assay, so I’m a
little skeptical.’ That’s fair enough but you have to allow someone to produce
a track record and produce preliminary data as well. If the preliminary data
doesn't look that good then you’re rightfully–and should be–concerned about
whether or not the person is capable of pulling off this project. But, you
cannot make decisions based on who the person is simply because you don’t know
them.

On the
flip side I've heard anecdotal stories that there are labs that at times, in
certain study sections, where they say, ‘Well that guy is at Howard Hughes, he
doesn't need any more money, so let’s give the money to someone else.’ As you
can imagine in this scenario, that converges into a middling type distribution
of grant money where perhaps some of those Howard Hughes investigators–well-funded
people–have other great ideas and there’s arguments to be made that they should
get more money to pursue those ideas. This should be done instead of giving
this to a lab that doesn't have a lot of funding, but they just have an okay idea.
There could be an argument that you could make the meritocracy work a little
better if you don’t know who anyone is. I’d be a proponent of the NIH doing
this, my caveat is that I’ve never sat on a study section, I don’t know what
it’s like. But, I feel that this change could have significant value.

SM: I loved your
blog post on Donald Trump and his interview where he spoke on autism and
vaccines.

NG: Oh, thank
you.

SM: His
interview was very… interesting.

NG: Yeah. Those
kinds of things are what irritate me most. I used to blog a lot more earlier on
in my editor career. I’ve kind of fallen off of it. Probably because I do
twitter too much…

NG: Thank you,
thank you. I’ve got to say that there are certain things that really kind of
razzle me. One of them are these kinds of miscommunications of science to the
public, especially when you have somebody where, even if people dislike him, he
is still known by a lot of people. It
doesn’t matter what your feelings are. He’s getting to a lot of people’s ears.
You have networks like Fox and those who are willing to put him on air to say
these things–and people can say these things–but it’s nice to have a counter.
So, I felt obligated to have a counter and say, well at least consider the
science. You have to consider not only the initial report–and people aren’t
even aware unfortunately that it has been retracted–but that there is a
controversy on this topic, even before it was retracted. And, so I think people
need to be aware of where these things sit in the community and that’s why I
felt I had to write that because it gets me upset. It’s so simple to provide
links to PubMed articles, people wouldn’t even have to read the full paper,
they could read the abstracts, which are right there and available. And most of
the information in those abstracts would negate almost everything Donald Trump
said in these interviews.

SM: I completely
agree with you. It was highly irresponsible of him. Especially, as you said,
with so many parents and people affected by this disorder and that becomes emotional.
And, to do that to those people, I was pretty upset as well.

NG: Yeah, and
that’s a really good point. You can’t always blame the people because it is
really emotional. They’re struggling with dealing with this disorder and
especially if they don’t have a significant science background.

SM: If you hear
something that sound reasonable, like the fact that we’re all vaccinated and
there are also so many people with autism, it might sound reasonable–as you said–to someone without a science background.

NG: Right.
Exactly. The thing is, I have to say is, if we didn't have the science behind it
to suggest that there aren't any problems with the vaccination schedule that we
have it does sound kind of scary that you do x number of shots. And, for a
non-scientist to say, ‘Woah, why are we sticking 30 shots into my kid within
the first six months of life?’...

SM: What’d
Donald Trump call it? A ‘monster shot’?

NG: Ha ha ha, oh
yeah! With all the shots in one. But again, science has reported that these
mercury-based preservatives in vaccines are a problem. But, we got rid of
those. And when we find problems with additives and such, there are a
procedures in place for science to correct that. Again, that’s based on science.

SM: And, it is reasonable that mercury-based
preservatives would have negative side-effects because mercury is very, very
toxic.

NG: Exactly. So
that’s the issue. Without these counterpoints out there, if Fox had run a
simple ad saying, ‘For more information on autism and vaccines, click here,’
the public isn't going to know that there are people who disagree with this
opinion. The problem is that a lot of sites that are notoriously known for
pushing this connection between vaccines and autism are one-sided in the
science they list. Journalists are in a good place because they have an
objective view to say, ‘Here are all of those sites with this opinion on autism
and vaccines but you should also take into account all of these sites,’ and let
people get informed. And if they still aren't informed after you give them
everything then there’s not much more
you can do. But, if you don’t give them the opportunity to inform themselves
then you can expect them to believe whatever Donald Trump says because you are
hitting an emotional button. You’re looking for something, you’re angry, you’re upset because you want the best for
your child. So it’s like, ‘Ah!’, let me point the finger at vaccines. So, I
understand it, but we need to stay better informed.

SM: Maybe Fox should hire you as their scientific consultant.

NG: Alright,
this is actually my interview for them.

SM: Ha ha ha.
Well, I actually work for Fox.

NG: Ha ha ha. Where are the hidden cameras?

SM: Ha ha.
Another reason I really enjoyed that article is that it is an obvious
reflection that you have your finger on the pulse of science news and a broad
understanding of science skepticism. It’s a healthy thing to have skepticism of
science news. I think this is an issue for people new in their training. It is
kind of a white elephant in the room, there’s so much literature out there, how
are they going to become so informed? What would you recommend to people that
are new in their training as far as habits for staying informed and more
up-to-date on their field, et cetera?

NG: There are
lots of options right now. And, more so than when I started out in grad school.
You pretty much had ‘e-talks’. Everybody got emails of the table of contents of
journals that they liked. They went after that, they’d read through and find
the papers that you thought were kind of important, you read those. Now we’re
in an era where PLOS ONE is extraordinary and publishing 30,000 articles a
year, I don’t know if that number is exactly correct but they’re in that
ballpark. And just getting an e-talk of PLOS ONE fills up your inbox. I feel
like you should still do the old-style way of selecting those few journals that
are relevant to your particular specialty, maybe pick out some more general
journals like Nature, like PNAS, or PLOS Biology that also cover a variety of
topics and see what they’re publishing. But after that, I’d recommend things
like Altmetric, PubPeer, and crowd-sourcing options that’ll bring your
attention to not only science to your particular field but as a trainee I think
it is always valuable to mature your scientific thinking and it doesn't
necessarily have to be about your field. I think you can read a lot by reading
through a debate–even if it is not in your field–between smart people on how to
interpret data because that is something as a trainee, you always need that.
Even a PI, you never stop evolving the way you think about science.

SM: Just like
journal club: a broad exposure to science outside your small field.

NG: Exactly. So
now we have online-journal clubs basically. We have journals like PubPeer,
which brings things to the forefront and all of these other options that I
mentioned. I think F1000 has options like this. Let’s just see what other
people, who are savvy about science are thinking about and I think you’ll learn
from it, even if it is not in your field. Find a couple of those websites and
hybrid with the old school e-talks. I’ve moved on to–and I guess this is still
old school–RSS feeds. I don’t get the emails anymore. I go to my RSS readers
and that’s how I get my tables of contents.

SM: Speaking of
new students and training, do you think someone early in their career should
aim for higher impact journals or publishing sooner so they can get funding and
get their name out there?

NG: So, that’s a
challenge. That’s a difficult question. I feel that the sooner a trainee can
get some experience with writing a paper and dealing with the review
process, the better. If you have a paper where you’re not sure if two years from
now it’s going to evolve into something really great, try to get it out. But,
this is also specific to the PI or the mentor. The mentor might have different
plans for the publication schedule than the trainee. But, if the trainee has
some strong inkling or some strong input into the publication schedule, I would
probably push for sooner. You know, there’s nothing like being part of this
engagement with your peers. I can’t tell you how much I learned from actually
chatting with reviewers, reading the reviews and responding to them. I think
that’s an invaluable experience to start engaging with your peers, meaning your
reviewers. Getting feedback on your work because there’s nothing like sitting
in the lab for four years and not getting any feedback. It’s nice to know that
what you’re doing matters to somebody else and it’s kind of exciting to get out
there. I feel–and this may only be my opinion, I may be absolutely wrong–that
publication record has less of an impact on how you get a post-doc. We know
it’s well-documented that it’s critical for getting a faculty position at this
time, if that is the route you’re choosing. But, it seems that people are
making their decisions on post-docs on fit between personalities, fit between
interests, fit between the academic goals, and you know, you can’t tell from
somebody’s publication record how good they’re going to be with their hands in
the lab. So, I feel that post-doc decisions are made much more smartly, more
soundly than tenure because you can’t predict anything from the publication
record. You don’t know if that person was first-author but, you know, did they really do all of those experiments? Was
there a technician that was just acknowledged and not even put on the paper who
really was the work horse or the hands? It’s invariable that as a post-doc that
you can’t move on until you get some stuff done in the lab. So if you go on to
this new lab and you’re not bringing your technician with you, you have to use
your fumbley hands again, you know? And, since you can’t predict that, you have
to go with these other things I mentioned, right? I feel like, of course the
mentor will look at the publication record; of course they do. But, I feel that
it is not as important on the final decision on who is going to get interviewed
or who they’re going to consider for the post-doc. With that in mind,
publishing sooner gives you so much more to be evaluated on that I would go for
that.

SM: Do you think
that models like F1000 has where you can publish your poster online is
something students should use?

NG: As long as
everybody who is a part of the project is on board for getting the data out
there in a public format I think that would be great. There’s F1000, there’s
the new bioRxiv that Cold Spring Harbor Lab Press just put out. You’ve heard
of arXiv, the physics e-print server, well this is a play off of that to support
biological sciences and allow a place for biologists to post things online as
well. You can post full papers, not just posters. They’re quickly assessed by a
panel of scientists to make sure that what’s posted is science. And, then it is
available for people to engage with, comment on, and discuss. These–I
believe–are going to be citeable; they’re going to get document identifiers. So
again, for things like this, as long as everyone is on board with it then I think
it’s a good thing.

We should also understand a bit of the history of these things. The
history of biology-based pre-print servers is not a good one. There have been a
number of them including a product produced by Nature that was operational for five years from 2007 to 2012 called Nature Precedings. Ultimately the
engagement flat-lined quite early in the project and never really came back and
then stopped accepting submissions. The take-up by biologists hasn’t been good
but that’s not a reason to stop. I still think Cold Spring Harbor is making the
right move by having this bioRxiv. F1000 is making the right move because
you cannot just throw something out just because it doesn’t get picked up
because we’re in a new technological age. You could argue that well, maybe that
was too soon. Just like certain things with paper commenting and different
forms of peer review that was tried in 2006 things by Nature and some others
that were deemed a failure, that people didn’t care to do them. But, maybe
people weren’t ready. The culture is changing to where we engage online,
discuss things online and now these conversations take place regularly online.
It’s now a natural thing to discuss science online whereas maybe in 2006 it
wasn’t. So, when someone back then tries it out and goes, ‘Woah, this is odd’
and they don’t pick it up. Now, it’s an obvious thing because you’re so used to
clicking ‘like’ and things that now it’s part of your work too. And, why not? I
would encourage it.

SM: Do you think
the friction or resistance of the academy to models like that might be the fear
of scooping?

NG: Yes,
absolutely. For most people that don’t want to put it out there, that
would be the number one reason. If
not, the only reason. Most of these archives are really good about updating and
informing people when the papers get published. They try to track them or
encourage the authors to write back when the papers do get published after the
pre-print so that they can immediately link to the final paper. So as long as
those kinds of links stay fresh and you have a paper trail then I don’t see
that as a problem. The fear of scooping is field-dependent. If you’re working
on an awake-behaving monkey for two years it is going to be hard to catch up
and scoop that study. But, a lot of molecular techniques like PCR or even data
analysis–with the newest push for putting source data online–might be far
easier to scoop. There are a lot of fields where computational analysis of data
sets will get you a paper. If you have somebody else’s data set out there that
you can use because they put it on a pre-print server you might be kind of
selling off one of your papers. And, you don’t know if you would’ve come up
with the idea without that data but that’s part of the argument as to why we
should put data on pre-print servers. Let the crowd figure out and put the best
science out. But, until it’s mandated I think people are going to be pretty
reluctant and hold on to what they perceive to be their intellectual property.

SM: Right and
you made a great point of how fast can someone reproduce your data is
proportional to how fearful you are of scooping.

NG: Scientists
are extremely paranoid individuals. And again, this is the culture that we’ve
created. I completely understand it and it’s definitely not a knock on the field
because if you need to have a Nature paper in order for a hiring committee to even consider
you, then you should be paranoid. That’s why I’m glad to see all of these pushes
because the more we can change a culture that goes beyond, ‘You’re only defined
by your x, y, and z publications,’ the better for science in general. To help de-stress
people and to allow for more sharing. To allow for people to place data out
there and say hey, ‘Well if someone gets a paper off of this, then great but it
is not going to ruin my career.’

SM: I actually
heard some offline comments this year at the meeting where people were
discussing people potentially doping in science just to stay awake long enough
to get more experiments out. And, to be able to get those kinds of publications
that would get you hired into the old-school tenure track.

NG: That’s
actually an interesting point. Nature actually covered that from the
perspective of undergraduates in college and not necessarily people in the lab.
That’s actually quite interesting.

SM: If you think
about it, they’re the ones spending a lot more time in lab that at some point is poor
for their health.

NG: Again, that’s
interesting and I wouldn’t be shocked.

SM: Me either
which is sad.

NG: I haven’t
heard it myself but it is definitely sad. And again, it all relates back to the
cul-… the intense pressure that we’ve created.

SM: Did you
almost say ‘cult’?

NG: Culture, ha ha. But I guess, same
thing–the intense pressure that we’re putting on people for the crunch for
positions and the crunch for funding which is one of the key things.

SM: You’re
obviously a highly skilled and experienced writer. I’m curious what you think of
your writing now compared to when you started grad school? How has it changed?

NG: I think that
the more I have read excellent science writers like Carl Zimmer, Ed Yong,
Virginia Hughes, people like that and Helen Pearson is another one that I learned
a ton from. She is the Chief Nature News features editor. She used to sit by me
in the office and we would discuss certain topics that we were considering for
features. Maybe she wanted my feedback, maybe I’d pitch a topic to hear and see
if she wanted to find a freelancer to take it deeper. I learned a lot from her
on how to put together a narrative to keep people’s eyeballs. When my writing
started with science, there’s a certain type of technical writing that
everybody does and I think that my style when I actually do write
something–which I don’t do much anymore–reflects what I’ve learned from these
writers about the narrative. There’s always a precipice where you have to
maintain that balance between not letting the narrative take too much of the
forefront but letting the science and
the narrative walk hand-in-hand together to engage the audience as opposed to
only the technical side or only the narrative. The danger of the technical side
is that you lose your audience right? Everybody stops reading. You know
nowadays people are click-happy and with one scroll, they’re gone. But also, if
you let the narrative get too far in front, then that’s when we see things that
are criticized for being put out in mass media where the science is not quite
there. And you had let the narrative run away it. You have to be careful to
make sure you are constantly keeping both hand-in-hand. I think that’s how my
writing has evolved by seeing what these other writers have done and try to
emulate that style and make it fit with my values of making sure the science is
always upfront as well and they do.

SM: You’re
speaking in terms of writing a non-technical article; not a primary article.

NG: Right, science
writing–popular science articles. But for manuscript-writing there’s a similar process.
For manuscript-writing, there’s not less of a narrative but it’s a different
narrative. What you might talk about in a story for the popular audience might
be based on some kind of human angle, something non-scientists can relate to.
The narrative in a manuscript is trying to captivate your scientific audience
and usually you captivate them by having a nice, clean, well-told story. That’s
not necessarily how the science always goes, right? It’s messy. I think from
the time from when I was a grad student, I had two good mentors both in grad
school and from when I was a post-doc who were great writers. They took care to
make sure that the message smoothly flowed and that you didn't try to over-hype your
results too much. You let the audience decide on what to think. You make
suggestions to lead people down through their thinking process but I think it’s
always important to let the audience make up their mind. That’s something we do
at Nature. We know what our readership is, how large it is and we’re a big
spotlight. So, if a paper doesn't have anything to do with autism and the
author has, ‘… and this might be interesting for autism,’ then we’ll remove
that because it is important to make sure that the facts drive the way. And in
a discussion of a manuscript, everybody knows that you can get a little looser. I think I had great training
on keeping it to the facts and letting those suggestions find a way to the
discussion and lead from there.

SM: Where do you
see yourself in ten years with Nature?

NG: Wow. I have
no idea. I enjoy my position in the community right now in which I am engaging
with a lot of smart people; I am discussing great science. I’m at a great
interface between scientists and great science communicators, like journalists
and other media-savvy people. Whatever I’m doing, whether it is at Nature,
whether it’s somewhere else, I want to have that type of interface. I like all
of these communities. I have a great engagement and interaction with scientists
and I like being able to be a bridge to bring the groups together. I really
hope whatever I’m doing in ten years, I still have that interface between popular
science communication and the hardcore science. I really don’t feel like I want
to drift toward one or the other too much. I want to stay at the interface and
interact with both. That’s the best I could do on that one.

SM: That’s a great
answer and it’s always interesting to hear people’s answers to that question.

NG: Ten years is
a long time. It’s been a little over ten years since PLOS was founded and there
have been massive changes with the way that the internet has driven science
communication and scientific debate. I can’t even imagine what another ten
years will bring. You could argue just since PLOS ONE, there have been
exponential changes and even the fact that everyone knows now what paper
commenting is. You don’t have to explain to them what post-publication peer
review is. We're at a place where things are rapidly going up and who knows what
the next ten years is going to give us. It’s exciting.

Indeed, our field of neuroscience and more generally, the field of science is quite exciting! Some of the news I covered at this year's Society for Neuroscience, along with my interviews of the people was an amazing part of the meeting that I was able to experience. I'm always happy to meet like-minded people that are passionate about science communication and making sure the public is informed about what scientists are doing and what it is that we do. Noah Gray's ability to communicate to the public reminds me of what my mentor from my first lab would say concerning your education, which is that if you have such a specialized and advanced education, it is your duty to educate. Not only because for most of us, the public subsidized a large portion of our education but because information like Noah provided on his blog post about the facts of autism and vaccines can literally save lives. Thanks again to Noah Gray for what I found–and hope you all find–to be a fascinating conversation that I had at this year's meeting.

Saturday, November 16, 2013

During the annual Society for Neuroscience meeting this year, I had the privilege to be one of the official meeting bloggers. Aside from covering some more of the traditional aspects to the meeting like posters, nano-, micro-, and full symposiums, I thought it might be interesting to some of my readers if I interviewed some of the people that are in attendance.

Announced this summer were the new building plans for the Allen Institute for Brain Science coming to the South Lake Union neighborhood of Seattle, Washington. In what is becoming the biggest basic neuroscience research powerhouse of the world, the institute is finally growing out of its first building and is expanding into a new one. This impressive structure appears to be best suited to help the institute on its mission to understand the human brain. So, I thought a key interview to conduct would be with Allan Jones, Ph.D., Chief Executive Officer of the Allen Institute for Brain Science. Dr. Jones graciously gave me over 30 minutes of his time at their wildly popular exhibit booth during the Society for Neuroscience meeting for this exciting interview on their work.

Steven Miller: What
makes the Allen institute different than academia, pharma, or biotech?

It's
tough explaining in it to people sometimes, like my fellow graduate students.

Allan Jones: Well
I'll give you a little bit of my speech when I talk to potential employees when
we're recruiting. I do think we're kind of this unique blend of what I always
say is the best of all worlds, which is that we get to approach science with
the discipline of industry. And so the organization as we built it was modeled
around a biotech company. That was my environment. I worked for a biotech
company, Merck a big pharma company. I like the discipline and approach that
you can take in this team-based science approach where truly you've got
products that you're trying to create and everybody is jointly working on them
together. We always talk about being multi-disciplinary but we truly are and
this atlas product is the collective work of PhDs in math, physics, IT, and all
of that. And it's been like a relay race where until the final product is done, we all succeed or fail. I think that's the thing that differentiates us most
from a traditional academic environment. The other thing that makes us unique is that what we pick to work on is done through advisory councils and that's where
a lot of collective decisions are made to say, 'What are the next interesting
things to work on as an establishment? What is the next direction for the
institute?' That's done in convention with a lot of external advice and input.
We have science advisory boards that are the premier scientists in their field
that come in. It's not a rubber stamp. We actually really want them to guide
and shape us. Another aspect that's different about us is that I'm the head of
the organization; I'm the CEO but it isn't about running my agenda. I think my
goal really is about building great teams, making sure we're aligned and obtaining
the resources we need and putting them in place to be able to execute.

SM: Unlike in the pharmaceutical industry where the
product is going to be directly obtaining revenue for you, how do you see your products obtaining revenue for the institute? Do you see them as a means to obtain public or private funding to continue work in the future?

AJ: This is
the beautiful part of what we get to do, because we're non-profit; Paul Allen
funds us for impact. Paul's return on investment is whether or not we have
impact on to field moving forward. We always have the metric of saying, 'How
can we best impact the field?' It allows you to sort of bulldoze and steamroll
a lot of the traditional way of doing things. We share anything. One of the
things I don't think people realize is that they use our atlases and all but,
three of the top ten all-time selling mice by Jax were produced at the Allen
institute. I think we have an openness of sharing of our tools, as well as the
data. Again, that return is all about having impact.

SM: I think
that's great because there are a lot of smaller groups and organizations trying
to push for open access, but not with the kind of financial backing of the
institute.

AJ: Right.
And, there are times at which, and something we trying to be very careful of is
that being the 800 pound gorilla, if you are an 800 pound gorilla you can...

SM: Stomp
out those little guys.

AJ: You just
have to be careful about how you want to use that. We've always said that that is what enables us to do things like helping the field move forward, help
establish standards and put this data out there. Sometimes the atlases and other
things act as frameworks around which people do the work. You can get caught up in
small decision making as opposed to saying, we're just going to do it. We're not
trying to take over the world, but it just needs to get done. We need to move
forward and get on with it.

SM: As
someone with a background in genetics, how do you think that's helped you at
the Allen institute?

AJ: I always
say it's a great devilish sword. Because the way the institute runs, I don't
have a dog in the fight. I don't have a neuroscience background. My background
included work on everything from C.
elegans to plants. I think biology is just cool. There are so many
interesting problems in biology and neuroscience is one of those areas. I just
want to have maximum impact. I don't have a pedigree. I'm not there to prove
any one theory or one way of doing things. Rather, what do we think–based on
what our scientists are saying, what our advisors saying–are the
best directions are to move forward.

SM: In terms
of advice for the habits of scientists and regarding your position as Chief
Executive Officer or Christof Koch's position as Chief Scientific Officer, what
would you tell people who are just starting out in their science training?

AJ: That's
an interesting question...

SM: Some
people say you should spend an hour on PubMed everyday to make sure you are
current on the literature. What are your habits?

AJ: My
habits were to be an omnivore.

SM: Ha ha.
Good answer.

AJ: I always
tried to cross-cut my ideas with others. I had a really good friend of mine in
grad school that was in a post-doc position that said, "The mark of a
great scientist is to believe in something passionately and have data change
your mind." I always liked that because it is really easy as scientists to
sort've get into your own dogma. Personally, for me, it is just more
interesting to try and keep an open mind.

SM: I
completely agree. People in science should be able to accept evidence in
disagreement of their dogma and that's often not the case.

AJ: Right.
One of the things I always enjoyed doing in undergrad was opening up my textbooks
and asking myself, "What is actually real?" When you look at all these
pictures in undergrad it feels like all you're learning are facts. When you get to
that higher level you start digging in and ask yourself, "What is the actual
evidence of the facts that I'm learning?" You should always be questioning
these things. The other thing I often tell people for data sharing and openness
is, if you only have one good idea in your career you are in the wrong field.
The people that I see in the field who hang onto things and their
piece, I don't see them really enjoying their work or ultimately having as much
impact. People who are more open and are involved in sharing their ideas enjoy
their work much more.

SM: On the
topic of sharing, what do you think of groups like Faculty of 1000 and how they
allow you to publish your research posters?

AJ: You
know, I'm a huge fan of overhaul in the publishing industry in one way, shape
or form. I think we need to take a look at how every other field has been
disrupted by technology. Ours is sort of ripe for the picking for being
disrupted in ways that can only help us do better science. I look at those
kinds of things and think about the coding community and all of their open
source-type work. They've developed mechanisms for that kind of sharing. There
are mechanisms for us to do it. The funding agencies could really get behind this movement and say, we need to live this. One of my
challenges is that a lot of organizations now are just giving lip service to
sharing. They don't necessarily live it. It's a hard thing to live. Sharing
your reagents or sharing you data goes a bit against human nature. But, you
just got to do it.

SM: Especially
now since some journals will say, hey we'll publish your article open access
but you have to pay more and that can be cost prohibitive for some labs to do
that.

AJ: The
challenge is that I understand from a business perspective that money has to
come from somewhere. One of the challenges is our field is always eager for the
things that are free or do not cost money but the reality is you have to spend
money. If you want to have great editors you have to pay them great salaries,
if you want to have great information dissemination somebody is going to have to pay. But, whether or not there are ways that this can be done differently, I'm
sure there are more people who think about that more than I do.

SM: Moving
on to talking about the ten year project of mapping and understanding the
visual system, would you say this project is exclusively part of the BRAIN initiative? Or, was this something the Allen Institute was planning on doing on
its own?

AJ: We were
doing it on our own. We started planning our ten year plan in 2010. Christof Koch came on board, we did another year with the planning and we launched our
initiative in March of 2012. A full year before the EU launched their project
or before the BRAIN initiative was talked about. As I like to say, what's significant
about the number 225? That's the number of panel discussions on the BRAIN
initiative that occurred in the last 6 months and the number of full-time
employees at the Allen Institute that are full steam ahead on our initiative. I
should clarify, because it's hard in short soundbytes to layout what our
broader plan is but there are elements to it that are continuous from our atlas
work. This initiative is all focused on cell types. Also, it's not just mouse,
it's mouse and human. We thought it was very important that ultimately we want
understand the human brain. In parallel to working on the mouse and describing
cell types in detail, we're working on human cell types as well. We have an
active program with a lot of resources going towards that program. A lot of
those studies are the ex vivo studies
we can do. For in vivo studies,
obviously in human they are very limited but we have active program, which we
intend to build around using human stem cells to make neurons in a dish. This
with the idea of being able to test some of the fundamental properties of human
circuits in a dish. That is a very long-term goal but I think that the
likelihood that you are ever going to be able to do an kind of invasive study
on a human to get down to that level is highly unlikely. We are going to need some kind of in vitro system to do
that. Then, of course the big thing is the MindScope part which is looking at
the awake behaving mouse and all of the activity that is going on in the visual
system and kind of systemically chipping away at understanding every
transformation that's going on.

SM: When the article came out in Neuron last year on how to map the brain and the
technologies we could use to do this, one piece of technology
discussed were the small synthetic cells that might attach and record activity
from human cells. What do you think of in terms of how feasible it might be for
getting these technologies approved? These technologies sound great but getting
them approved by an IRB, that's challenging.

AJ: Are you
going to be the one to sign up?

SM: No, I
don't think I will.

AJ: The
reality is I think it is going to be somewhere in the middle. The thing that I
always marvel at is the statistic now that there are over 100,000 people on
this planet that have implanted devices in their brains and that number is only
going up. The analogy I like to make is to a pacemaker in your heart. So
if you told people 40 years ago that we are going to put an electronic device
on your heart and it is going to control its beating, I'm sure the reaction
then was, 'no way', 'that's crazy', 'I'm not going anywhere near that.' Now,
it's an outpatient procedure, it's easily done, and the battery lasts a very
long time. Whether or not people are going to accept an injection with little
nanobots that crawl your brain, I'm not sure but I see it moving in that
direction.

SM: I think
it was two years ago when Ed Boyden gave his TED talk on optogenetics discussing how that technology could be used as a pacemaker for the brain in the case of
epilepsy. It could detect seizures, turn on and stop the seizure activity dead
in its tracks. If I had epilepsy, I would be very interested in this and I
think it is the kind of use case where I think people would want to sign up.

AJ: Right
and I think that's exactly the case with people that have severe Parkinson's
disease. These are the kinds of things where I think about how people can have
depression so debilitating that they would get a pacemaker implanted in their
brain but so many people are. And, it has actually been shown to be quite
effective. That said, maybe some of the non-invasive methods are going to get
so good that there will be improvements there.

SM: So let's say you accomplish your ten year mission, what do you see as what's next?

AJ: There we
would be on the cusp of saying–broadly speaking–what the principles are for the
language of the brain. 100 years ago the language of chemistry was unfolded. 50
years ago was DNA and information coding. Now, you're 50 years later and I
think all of the technologies are here. I mean, look there are 30,000 of us
here working on the brain. We ought to be able to do this. There are going to
be general principles learned. Then the challenge will be now that we
understand that toolkit, we understand that basic language, how does the human
brain work? I think that is sort of our ten years and beyond. I think what
we're going to get over the next ten years is an of understanding of that
language...

SM: And
applying it to other systems?

AJ: Applying
it to understand the basics of human computation and go from there. I think a
lot would have to be done in vitro, which
is why we are trying to prepare ourselves to do that so you can test a
hypothesis.

SM: Vision
is the most heavily researched of the special senses. What is the Allen
institute going to provide to that field that is not already known? People have
studied retina, studied visual cortex, etc...

AJ: Sure but
if that's the case, explain to me how vision works. It's not a knock on all great work that's been done
but one of the things we can do as the 800 pound gorilla is to approach
this systemically. One of the challenges, as you said, great vision work has been done but one group will find one thing and one group find a different
thing and this is probably due to non-standard conditions or something like
that. We have the ability to do it all in one place, all in one shot and
systemically march through all of the information transformations. Paul Allen
and the institute is making the bet that that is going to be the path forward.
You’re going to need to put all of that knowledge together so you can iterate
on it and be able to test your hypotheses. Then, you can go back and gather
data in iterative ways that will require big data sets. Not just recording
from a handful of cells but all cells. Then, mapping them functionally, seeing
who they're connected to and putting all of that data together and doing it over
and over and over again. I think those are the kinds of things that we are
pretty uniquely set up to do.

SM: Especially
since it would be very challenging for an academic lab to do this kind of work.

AJ: It’s the
kind of work where the scientific challenges are matched equally by the
operational challenges. It may sound easy for people to scale but it’s not. It
is exceptionally difficult.

SM: I talked
to Jim Berg last night who is running the slice electrophysiology core and I
was very excited because this is the kind of work I do. So, hearing some
details about how this is going to be set up at the institute was fascinating.

AJ: Jim cracks
me up because he’s one of those people where we are getting him to be a
believer. He had that same sort of notion that electrophysiology is like an
art. Everybody said that about in situ
hybridization, ‘You can’t have a technician doing in situ, you need your best post-doc with tender, love and care to
be able to do this.’ I would say that if that is the case, you are doing
something wrong. You’re just not systematic enough about it. Any process can be
automated and systematized.

SM: I think
that it is very important that the field does standardize conditions, especially
for electrophysiology. In the literature, as you said with vision research, one
lab finds one thing, one finds another and no one is publishing enough methods
details so it can be easily replicated.

AJ: Right.
That’s why our thing is, we will put it all out there. You will see exactly
what our protocols are, exactly what we did. You can have at the data, you can
see what models we’ve run. The idea would be ultimately to have an online
community that is there going back and forth saying, ‘What if we tried this
parameter?’ Then we could run it and comment what our result was and it didn’t
work so well, or it added to the improvements. Now, let’s add that and keep it.

SM: That is why
I think the white papers available on your website are great. It is the level
of detail for methods that needs to be published but that publishers do not give
you the room for. The work the institute is doing is excellent. Thank you for your time today.

If Paul Allen's bet is right, this is the place where the brain is going to be unlocked. I hope you all found my interview of Allan Jones to be as interesting as I did. For anyone interested in neuroscience and the brain, this organization is who you should be watching over the next decade and beyond.